Semicarbazones having CNS activity and pharmaceutical preparations containing same

ABSTRACT

A compound of general formula I below useful as an anticonvulsant for disorders of the central nervous system:                    
     wherein: R 1 , R 2 , R 3  and R 4  may be the same or different and each represents a hydrogen or halogen atom, or a C 1-9  alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy group; R 5  represents a hydrogen atom or a C 1-9 alkyl, C 3-9 cycloalkyl or C 6-10 aryl group; and X is oxygen or sulfur; or a pharmaceutically-acceptable salt thereof. The compound may be adimistered orally for treating convulsions in humans or animals.

BACKGROUND OF THE INVENTION

I. Field of the Invention

This invention relates to semicarbazone compounds having central nervoussystem (CNS) activity and to pharmaceutical preparations containing suchcompounds. More particularly, the invention relates to semicarbazoneshaving anticonvulsant properties and to the use of such semicarbazonesfor the treatment or prevention of convulsions and seizures in humansand animals.

II. Description of the Prior Art

There has been a great deal of interest for many years in theidentification of drugs that exhibit central nervous system activity inhumans and animals and that are, in particular, anticonvulsants used forthe treatment or prevention of epileptic seizures and other centralnervous system disorders.

A previous study carried out by one of the inventors of the presentinvention (Dimmock et al., J. Med. Chem., 1993, 36, pp. 2243-2252)revealed that a number of aryl semicarbazones of the general formula A

possess anticonvulsant activity in the maximal electroshock (MES) screenand the subcutaneous pentylenetetrazole (scPTZ) screen when administeredby the intraperitoneal route to mice. These screens are test systemsdeveloped to detect compounds which will afford protection togeneralized tonic-clonic seizures and generalized absence convulsions,respectively. The MES screen and the scPTZ screen have been discussed byKrall, et al. in “Antiepileptic drug development:II. Anticonvulsant drugscreening”, Epilepsia, 1978, 19, pp. 409-428; the disclosure of which isincorporated herein by reference.

Nevertheless, the compounds of formula A displayed neurotoxicity whenadministered by this route and the protection indices (PI, namely theratio TD₅₀/ED₅₀) of ten representative compounds were low.

There is accordingly a need for compounds showing much improvedanticonvulsive effects with reduced toxicity.

SUMMARY OF THE INVENTION

An object of the invention is to provide compounds having centralnervous system activity.

Another object of the invention is to provide pharmaceuticalcompositions that have good anticonvulsive activity and acceptableneurotoxicity.

Yet another object of the invention is to provide methods of treatingconvulsions in humans and animal patients without producing unacceptableside effects.

According to one aspect of the invention, there is provided a compoundof the general formula I

wherein: R¹, R², R³ and R⁴ may be the same or different and eachrepresents a hydrogen or halogen atom, or a C₁₋₉alkyl,C₅₋₉cycloaliphatic, cyano, C₁₋₉alkoxy or C₆₋₁₀aryloxy group; R⁵represents a hydrogen atom or a C₁₋₉alkyl, C₃₋₉cycloalkyl or C₆₋₁₀arylgroup; and X is oxygen or sulfur. In the compounds of the invention, thealkyl substituents, when present, may be straight-chained or branched.

It should be noted, however, that the compound of Formula I above inwhich R¹, R², R³, R⁴ and R⁵ are all hydrogen is known from Tomita et.al., “Synthesis of Aldehyde Derivatives Containing a Diphenyl EtherNucleus”, J. Pharm. Soc. Japan, 1955, 75, 1021-1023, but this referencedoes not disclose the anticonvulsive property of the compound.

According to another aspect of the invention, there is provided acomposition comprising a compound of general formula I and apharmaceutically acceptable diluent, excipient or carrier.

According to yet another aspect of the invention, there is provided amethod of treating diseases of the central nervous system of a human oranimal patient, which comprises administering to said patient aneffective amount of a compound of general formula I.

The compounds of the invention may be administered orally and mayexhibit very high potencies against CNS convulsions, e.g. they maypossess ED₅₀ figures (for the maximal electroshock screen in rats) inthe 1-5 mg/kg range (more usually the 2-3 mg/kg range) while exhibitingan absence of neurotoxicity at the maximum dose utilized (e.g. 500mg/kg), thus leading to extremely favourable protection index (PI)values.

The compounds of the invention appear to act by one or more mechanismswhich are different from those of conventional anticonvulsant drugs.Moreover, the compounds of the invention may be free from some of thedisadvantages of conventional anticonvulsant drugs since proconvulsantproperties and effects on the activities of certain hepatic enzymes areabsent in at least some of the compounds of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified representation of the postulated receptor siteshowing different binding regions for the compounds according to thepresent invention;

FIG. 2 shows basic skeletal structures to indicate the compounds listedin Tables 1 to 3; and

FIG. 3 shows basic chemical structures to indicate the compounds listedin Tables 4 to 6.

DETAILED DESCRIPTION OF TEE PREFERRED EMBODIMENTS METHODS OF SYNTHESIS

The compounds of the present invention and compounds having relatedstructures can be synthesized by various chemical routes, e.g. by amodification of a method disclosed by Yeager et al. (“A ConvenientMethod for the Preparation of 4-Aryloxyphenols”, Synthesis, 1991, pp.63-68; the disclosure of which is incorporated herein by reference).Yeager et al. describes a process for producing aryloxybenzaldehydes oraryloxyaryl ketones. These intermediates may then be reacted withsemicarbazides. This route is illustrated by the reaction scheme below:

The reaction scheme shown above requires the formation of intermediatearyloxy- or arylthio-benzaldehydes or ketones by reacting appropriatephenols or thiophenols with fluorobenzaldehyde or fluoroaryl ketones ina suitable solvent (e.g. dimethylacetamide) in the presence of anhydrouspotassium carbonate at temperatures in the range of 100° to 200° C.under atmospheric pressure of a non-oxidizing gas nitrogen) with refluxfor a period of about 5-10 hours. After cooling and water addition, theintermediate compound may be extracted with an organic solvent (e.g.chloroform) and dried. The intermediate aryloxy(thio)benzaldehydesaryloxy (thio)aryl ketones are then converted into the desiredsemicarbazones by reaction with semicarbazide in an aqueous ethanolicsolution for a period of one to several hours at ambient temperature,and the resulting precipitate of the final product is then collected andrecrystallized. The starting materials, which are generally reacted inapproximately stoichiometrical amounts, are themselves commerciallyavailable products and can, in particular, be obtained from the AldrichChemical Company, Milwaukee, USA.

Structures

Without wishing the invention to be limited to a particular theory, itis believed that the compounds of the present invention exert theiranticonvulsive activity by aligning their molecules at a postulatedreceptor site in the human or animal brain, and it is theorized thatsuch interactions take place at three areas of the receptor, namely anaryl binding site, a hydrogen bonding area and a distal binding site asillustrated in FIG. 1.

These sites are believed to react with the proximal aryl ring (the ringnext to the semicarbazono group), the semicarbazono (H₂NCONHN═) groupitself and the distal aryl ring of the compounds, respectively. Thepresence of the distal aryl ring and certain substituent groups on thedistal and, to a lesser extent, the proximal aryl ring in the compoundsof the invention appear to strengthen the attachment of the molecule atthe receptor and thus increase the potency of the compounds.

A systematic synthesis and evaluation of compounds of Formula I andcompounds with closely related structures has revealed the followinggeneral principles

(i) The substitution of the methine hydrogen attached to the carbiminocarbon atom by larger groups does not significantly affect theanticonvulsive activity of the compounds; (ii) positioning of thearlyoxy or arylthio group in the ortho or meta positions of the proximalring leads to a lowering or abolition of anticonvulsive activity; (iii)the substitution of the ether oxygen by sulfur or sulfonyloxy groupsleads to compounds with similar anticonvulsive activities, while otherspacers lower the anticonvulsive potencies; (iv) a decrease in size ofthe substituents on the distal aryl ring, increases anticonvulsiveactivity; and (v) the anticonvulsive activity is high when at least oneof the substitutents on the distal alkyl group is in the para position.

Hence, compounds of the present invention which are particularlypreferred are those in which R¹ and R² are hydrogen or halogen (mostpreferably fluorine), R³, R⁴ are each hydrogen and R⁵ is hydrogen orC₁₋₃ alkyl, and X is O or S (and most preferably O).

Particularly preferred compounds according to the present invention are4-(4′-fluorophenoxy)benzaldehyde semicarbazone and4-(thiophenoxy)benzaldehyde semicarbazone. These compounds exhibit highactivity in the MES screen, low toxicity and afford protection in thecorneal kindled rat screen without negative features, such asproconvulsant properties. Incidentally, the kindled rat screen isdescribed by R. J. Racine in “Modification of Seizure Activity byElectrical Stimulation. II. Motor Seizure”,Electroencephalogr.Clin.Neurophysiol., 1972, 32, 281-294, and by G.Skeen et al. In “Development of Kindled Seizures Following ElectricalStimulation via the Cornea”, Soc.Neurosci., 1990, 16(1), 307; thedisclosures of which are incorporated herein by reference.

Physiological Activity

The compounds of the present invention may in some cases have quite highneurotoxicity when injected intraperitoneally in mice. For example,neurotoxicity was found to be present in approximately 65% of thecompounds tested and quantitation of the bioactivities of the compoundsof the invention has revealed PI's in the range of 2-14 in the MESscreen and 1-3 in the scPTZ screen. However, it has been found that suchneurotoxicity disappears or is reduced to an acceptable level when thecompounds are administered orally to rats. Moreover, while the compoundsexhibit high activity in both the MES screen and the scPTZ screen whenadministered intra-peritoneally, the activity in the MES screen remainshigh when the compounds are administered orally, but the activity in thescPTZ screen may decline. For example, for the compound4-(4′-fluorophenoxy) benzaldehyde semicarbazone, oral dosing of ratsproduced an ED₅₀ figure in the rat oral screen of 1.59 mg/kg and a PI ofgreater than 315. However, the compound did not afford protection in thescPTZ screen at a dose of 125 mg/kg and only 10% of the rats wereprotected at a dose of 250 mg/kg. An absence of neurotoxicity at themaximum dose utilized (500 mg/kg) led to exceptionally high protectionindices.

Administration

The compounds of the invention may be administered orally to humans,preferably at dosages of 50-75 mg/kg, generally in the form ofcompositions with inert pharmaceutically-acceptable compounds, forexample diluents (e.g. calcium phosphate dihydrate, calcium sulfatedihydrate, cellulose, dextrose, lactose, mannitol, starch, sorbitol,sucrose and sucrose-based materials), binders and adhesives (e.g.acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone(PVP), alginates, sorbitol, pregelatinized starch or starch paste andtragacanth), disintegrants (e.g. alginates, cellulose and cellulosederivatives, clays, cross-linked PVP, starch and starch derivatives),lubricants (e.g. polyethylene glycols, stearic acids, salts andderivatives, surfactants, talc and waxes), glidants (cornstarch, silicaderivatives and talc), and colors, flavors and sweeteners (e.g. FD&C andD&C dyes and lakes, flavor oils and spray-dried flavors, artificialsweeteners and natural sweeteners).

The compositions may be prepared in any one of the conventional formsfor oral administration, e.g. powders, capsules, tablets, caplets,lozenges, solutions, syrups, etc.

The invention is described in more detail in the following Examples,which are nevertheless not intended to limit the scope of the invention.

EXAMPLE 1

The compounds 2a to 5v shown in Table 1 below were synthesized by themethod previously mentioned. The structures of the listed compoundscorrespond to those shown in FIG. 2 identified by the same first number(2, 3, 4 or 5), with only the substituents being identified in Table 1.

TABLE 1 Aryl Substituents, Physical Data and Anticonvulsant Evaluationafter Intraperitoneal Injection into Mice and Oral Administration toRats of the Compounds in Series 2-5 intraperitoneal injection inmice^(a) MES acPTZ toxicity oral administration to rats^(b) aryl yieldscreen screen screen dose MES screen compound substituents m.p.(° C.) %0.5 h 4 h 0.5 h 4 h 0.5 h 4 h (mg/kg) 0.25 h 0.5 h 1 h 2 h 4 h 2a H198-199 40 — — — — — — 50 — — 2 1 1 2b 4-F 210-212 48 — — — — — —  30 00 1 2 4 3 H 224-225 70 — 300 — — — — 50 — — — — — 4a H 224-225 60 100300 — — — — 50 — 3 4 4 4 4b 4-F 233-234 65  30 100 — — — — 50 2 4 4 4 44c 4-Cl 225-226 40  30  30  30 — 300  30 50 4 4 4 4 4 4d 4-Br 225-226 60 30  30 — — 300  30 50 1 4 4 4 4 4e 4-I 221-222 71  30  30 100 300 300100 50 3 4 4 4 4 4f 4-CH₃ 219-221 50  30 100 — — — — 50 3 4 4 4 4 4g4-C₆H₅ 280 72 — 300 — 300 — 300 12.5 — — — 3 1 4h 4-OCH₃ 218-220 60 100100 — — — 300 50 — 4 4 4 4 4i 4-OC₆H₅ 209-210 55 — 300 — — — — 50 — — —1 1 4j 4-CN 218-220 40  30  30  30  30 300 100 12.5 2 4 4 4 4 5a 2-F228-230 42 100 300 300 — — — 50 2 4 4 4 4 5b 3-F 209 42  30 300 100 —300 300 50 4 4 4 4 4 5c 2,3-F₂ 225 50 100 100 300 — — — 12.5 - 3 4 4 45d 2,4-F₂ 229-230 42  30  30 100 — — — 50 3 4 4 4 4 5e 2,5-F₂ 230 65 100300 100 — 300 300 12.5 — 1 1 4 1 5f 2,6-F₂ 232 30  30  30 300 300 300300 12.5 0 2 4 4 4 5g 3,4-F₂ 212-213 86 100  30  30 300 — — 50 2 4 4 4 45h 2-Cl 207-208 42  30  30 100 300 300 — 50 3 4 4 4 4 5i 3-Cl 185-186 35 30 100  30 300 300 100 50 — 4 4 4 3 5j 3,4-Cl₂ 216-217 45 300  30 — — —300 50 — 2 4 4 4 5k 2-F, 4-Cl 225-226 60  30  30 — — 100  30 12.5 2 4 44 4 5l 2-Cl, 4-F 209-210 59  30  30 — — 100 300 50 4 4 4 4 4 5m 2-Br,4-F 203-205 40 100 100 300 — 300 300 50 4 4 4 4 4 5n 2-CH₃ 205 25  30100 100 100 300 300 12.5 — 4 3 4 4 5o 3-CH₃ 205-206 35  30 100 — — 100300 12.5 — 4 4 3 2 5p 4-C₂H₅ 210 40  30  30 300 — 300 100 12.5 — 2 4 4 45q 4-n-C₃H₇ 215 53 100 100 300 — — 300 12.5 — 1 2 4 2 5r 4-n-C₄H₉192-193 38 100  30 — 100 300 100 12.5 — 2 2 3 4 5s 4-t-C₄H₉ 200-202 48100  30 — 100 100 100 12.5 — — 4 4 4 5t 4-t-C₈H₁₇ 190 30 — — — — — 300 −− − − − − 5u 4-O-n-C₄H₉ 203 35 300 100 300 300 300 300 12.5 — — — — 2 5v4-O-n-C₇H₁₅ 204-206 20 — — — — 300 − − − − − − − Phenytoin  30  30 — —100 100 − − − − − − Carbamazepine  30 100 100 300 100 300 − − − − − −Valproic acid — — 300 — — — − − − − − − ^(a)Doses of 30, 100 and 300mg/kg were administered. The figures in the table indicate the minimumdose whereby bioactivity was demonstrated in half or more of the mice.The animals were examined 0.5 h and 4 h after injections were made. Thelines — indicate an absence of anticonvulsant activity andneurotoxicity. ^(b)The figures in the screen indicate the number of ratsout of 4 which were protected. The lines — mean that no activity wasdemonstrated and the designation − indicates that the compound was notscreened.

The details of the syntheses of the various compounds are indicatedbelow.

Synthesis of Intermediates

The 3-phenoxybenzaldehyde used as a starting material required in thesynthesis of compounds 3 was obtained from the Aldrich Chemical Company,Milwaukee, Wis. The intermediate aryloxyaryl aldehydes required in thesynthesis of the other compounds were prepared as follows. Anhydrouspotassium carbonate (0.12M) was added to a solution of the appropriatephenol (0.15M) and 4-fluorobenzaldehyde (0.14M) in dimethylacetamide(100 mL). The mixture was heated under reflux at 155° C. under nitrogenand the progress was monitored by thin layer chromatography (TLC) usinga solvent system of benzene:methanol (9:1 by volume). Afterapproximately 5-10 hours, the mixture was cooled and water (100 mL) wasadded. The reaction mixture was extracted with chloroform (2·100 mL) andthe combined organic extracts were washed with aqueous sodium hydroxidesolution (4% w/v) and water. After drying over anhydrous magnesiumsulfate, the solvent was removed in vacuo and the resultant oil wasdistilled under reduced pressure to give the appropriate aryloxyarylaldehyde. The purity of the distillate was checked by thin layerchromatography (TLC) using benzene:methanol (9:1 by volume) as thesolvent. The ¹H NMR spectrum of a representative intermediate, namely4-phenoxybenzaldehyde, was as follows: δ(CDCl₃):9.94(s,1H, CHO),7.82-7.88 (2t,2H,ortho H of proximal aryl ring), 7.38-7.46 (3t,2H,meta Hof proximal aryl ring), 7.20-7.27(3t,1H,para H of distal aryl ring),7.03-7.12 (3t,4H, ortho and meta H of distal aryl ring).

Synthesis of Final Compounds

A mixture of semicarbazide hydrochloride (0.01M), sodium acetate (0.01M)and water (10 mL) was added slowly to a stirring solution of thearyloxyaryl aldehyde (0.01M) in ethanol (95%, 30 mL). The reactionmixture was stirred at room temperature for 1-2 hours, the precipitatewas collected, washed with ether, dried and recrystallized from 95%ethanol (compounds 3, 4b, 4e, 4h, 5b-3, 5k-e, 5v), absolute ethanol(compounds 4a, 4c, 4d, 4g, 4i, 5a, 5fj ,5u) or methanol compound (4f).

The literature melting point (° C.) of compound 4a was 219°-220° C.

The melting points indicated for the various compounds are uncorrected.Elemental analyses (C,H,N) are were within 0.4% of the calculated valuesexcept for compound 5n (calcd. for C₁₅H₁₅N₃O₂:N,15.60. Found: N, 14.80).¹H NMR spectroscopy was undertaken using a BRUKER AM 300 FT (trademark)NMR instrument. Thin layer chromatography (TLC) was performed usingsilica gel sheets with a fluorescent indicator.

EXAMPLE 2

An initial anticonvulsant evaluation of the compounds prepared accordingto Example 1 was undertaken by administering the compounds by theintraperitoneal route to mice. Protection and/or neurotoxicity was noted0.5 and 4 hours after administering doses of 30, 100 and 300 mg/kg ofeach semicarbazone to the animals. These results are presented in Table1 above.

All of the compounds were active in the MES screen except compounds2a,b,5t,v and protection was afforded by 60% of the compounds in thescPTZ test. Neurotoxicity was displayed by approximately 70% of thesemicarbazones. Bioactivity was quantitated for selected compounds andthese data are given in Table 2 below:

TABLE 2 Evaluation of Selected Compounds in the MES, acPTZ andNeurotoxicity Screens after Intraperitoneal Injection in Mice MES screenacPTZ screen neurotoxicity screen PI Com- pound t (h) ED₅₀ (mg/kg) (95%CI) slope (SE) t (h) ED₅₀ (mg/kg) (95% CI) slope (SE) t (h) TD₅₀(mg/kg)(95% CI) slope (SE) $\left( \frac{{TD}_{50}}{{ED}_{50}} \right)_{MES}$

$\left( \frac{{TD}_{50}}{{ED}_{50}} \right)_{scPTZ}$

4b 1 12.86 8.28 1 >54 — 1 108.03 3.69 8.40 — (10.54- (3.00) (71.52-(0.96) 17.09) 157.52) 4f 1 14.65 5.59 1 88.55 1.87 2 203.73 4.29 13.912.30 (10.44- (1.91) (45.52- (0.57) (132.44- (1.31) 19.23) 173.94)271.13) 5a 0.5 20.69 18.59 0.5 >220 — 2 170.01 12.36 8.22 — (18.68-(5.63) (146.81- (3.80) 22.14) 191.65) 5c 1 45.78 15.53 1 >350 — 2 292.555.78 6.39 — (41.39- (5.71) (209.59- (1.77) 52.15) 379.29) 5d 0.25 11.252.78 0.25 57.85 1.70 1 96.81 11.50 8.61 1.67 (6.68- (0.86) (30.13-(0.54) (77.60- (4.08) 19.16) 93.95) 113.81) 5g 1 14.48 4.62 0.5 72.784.27 2 94.80 3.17 6.55 1.30 (9.53- (1.35) (49.01- (1.34) (59.86- (1.09)18.91) 99.12) 156.29) 5i 0.5 27.69 6.01 0.5 41.16 3.53 2 64.48 4.54 2.331.57 (20.39- (2.08) (26.98- (0.91) (42.03- (1.36) 36.12) 56.74) 84.72)5l 1 13.12 3.12 1 >68 — 1 62.46 15.48 4.76 — (8.70- (1.03) (55.56-(4.84) 20.12) 67.86) 5q scheduled 5p scheduled 5r 4 13.36 6.945 1 86.9311.442 4 131.27 6.467 9.825  1.510 (10.393- (2.045) (71.514- (4.493)(110.848- (1.703) 16.258 108.966) 158.464) 5s 4 8.87 13.063 4 >150.00 —4 105.92 6.313 11.934 >0.076 (7.704- (3.833) (85.053- (1.976) 4.957)142.591) 5t 2 11.27 10.881 2 >200 — 2 124.53 3.924 11.048 >0.623 (8.313-(4.272) (81.064- (1.095) 12.872) 175.187) Phenytoin 1 6.32 11.24 1 >50 —0.5 41.23 14.39 6.52 — (5.44- (3.52) (36.90- (4.82) 7.23) 46.14) Carba-0.25 9.85 20.8 0.25 >50 — 0.25 47.8 7.98 4.85 — mazepine (8.77- (7.15)(39.2- (2.37) 10.7) 59.2) Valproate 0.25 287 7.31 0.25 209 8.51 0.25 48312.3 1.68 2.31 (237- (2.48) (176- (2.69) (412- (4.01) 359) 249) 571)

The majority of the compounds were examined for oral activity in rats.Initially doses of 50 mg/kg of the semicarbazones were administered.However as the data in Table 1 reveal, with the exception of compound 3,all compounds examined at this dose displayed activity in the MESscreen. In an attempt to discern those compounds possessing marked oralactivity, the dose was reduced fourfold to 12.5 mg/kg, revealing thatprotection in the MES screen was retained in all cases. Using the dosesindicated in Table 1, neurotoxicity was absent during the 0.25-4 hourtime period with the exception of compound 51 in which case ¼ ratscaused neurological deficit 1,2 and 4 hours after oral administration.Compounds 4e,5b,d,g-i,n,g,r were evaluated in the scPTZ screen at thedoses indicated in Table 1 but they were either inactive (compounds5b,d,g,i,g) or displayed only marginal activity, details of which aregiven below. Quantitation of selected compounds was undertaken and thefigures obtained are presented in Table 3.

TABLE 3 Evaluation of Selected Compounds in the MES and NeurotoxicityTests after Oral Administration to Rats MES screen neurotoxicity screenED₅₀(mg/kg) slope TD₅₀(mg/kg) slope Compound t (h) (95% CI) (SE) t (h)(95% CI) (SE) PT^(a) 4b 2 1.59 3.17 ¼-24^(b) >500 — >315 (1.01-2.25)(0.84) 4f 2 3.43 4.121 2 >500 >145.57 (2.282-4.726) (1.324) 5c 4 6.152.55 — — — — (3.69-9.71) (0.69) 5e 2 11.44 4.12 — — — —  (7.61-15.75)(1.32) 5g 4 2.37 3.18 ¼-24^(b) >500 — >210 (1.54-3.62) (0.81) 5k 4 1.132.661  >90 >79.179 (0.713-2.005) (0.949) 5n 2 5.65 3.65 ¼-24^(b) >500— >88 (3.79-7.81) (0.98) 5o 1 3.07 7.114 >500 >162.47 (2.579-3.944)(2.292) 5p 6 6.48 1.98 — — — —  (2.970-15.536) (0.753) 5q 2 2.633.213 >500 >190.02 (1.689-3.926) (0.819) 5r 4 3.21 3.575 >3.22 >100.16(2.252-4.636) (1.022) 5s 4 1.68 4.437 >500 >297.24 (1.146-2.438) (1.281)5u 4 45.81 1.327  (19.481-315.522) (0.524) Phenytoin 2 23.2 15.1¼-24^(b) >500 >21.6 (21.4-25.4) (4.28) Carba- 1 3.57 3.84 1  361 11.4101 mazepine (2.41-4.72) (1.15) (319-402)  (2.96) Valproate 0.5 395 8.13  0.5  859 6.57 2.17 (332-441) (2.76) (719-1148) (2.17) ^(a)PI indicatesthe protection index i.e. TD₅₀/ED₅₀. ^(b)The compound was examined 0.25,0.5, 1, 3, 4, 6, 8, and 24 h after administration.

Further bioevaluations of compound 4b were undertaken. Afterintraperitoneal injection into rats, the ED₅₀ and TD₅₀ figures in theMES and neurotoxicity screens for 4b were 2.37 and 80.09 mg/kgrespectively revealing a PI of 33.8. Using a kindled rat screen, theED₅₀ figure of this compound was 3.93 mg/kg. A daily dose of 100 mg/kgof 4b was administered orally for three days to rats. Afterwards, thelivers were removed and comparisons made between the hepatic tissue fromtreated and control animals, namely liver weights and microsomal proteinyields in addition to the enzyme activities of cytochrome P450,p-nitroanisole O-demethylase, UDP-glucuronosyl transferase,sulfotransferase, ethoxyresorfin O-deethylase, pentoxyresorvfinO-dealkylase, glutathione S-transferase and quinone reductase. Nodifferences in the properties between the livers from treated andcontrol livers were detected (p>0.05).

Both 4b and 5g were examined for proconvulsant properties in theintravenous pentylenetetrazole test in mice; the doses administered werethe MES ED₅₀ and the TD₅₀ figures of 4b and 5g indicated in Table 2.Neither compound possessed this undesirable feature and using a dose of108 mg/kg, 4b increased the time to clonus. Compounds 4b and 5g werealso evaluated for their ability to prevent convulsions induced by thesubcutaneous administration of bicuculline and picrotoxin in mice. Thesemicarbazone 4b gave partial protection in these two screens whereas 5gwas inactive. In addition 4b afforded no protection in the subcutaneousstrychnine test in mice.

Full details of these tests are provided below.

Intraperitoneal Injection in Mice

In addition to the information summarized in Table 1, intraperitonealinjection of a number of compounds into mice elicited the following sideeffects at various doses (mg/kg) and time intervals. First, in the scPTZscreen, myoclonic jerks were noted with the following compounds namely4c:30,100;0.5h and 5f: 100,300;0.5h. Second continuous seizure activitywas observed in the scPTZ screen as follows: 4c:300;0.5h; 100,300;4h;4d:100,300;0.5 and 4h;4i:100,300;0.5 and 4h;5i:300;0.5h; 51:300,0.5 and4h;5o:100,300;0.5h and 5s:300;4h. At the end of the 4 hours, continuousseizure activity followed by death resulted in the scPTZ screen whenmice received 300 mg/kg of 5o.

Oral Administration to Rats

Using the doses indicated in Table 1, several compounds showed marginalactivity in the scPTZ screen. These compounds as well as the number ofrats protected at different time periods are as follows: 4e.:1/4 after0.5,1,4h; 5h:1/4 after 4h; 5n:1/4 after 0.5,1,2h and 5r: 1/4 after 1,4hand 2/4 after 2 hours.

Intraperitoneal Injection of Compound 4b in Rats

The ED₅₀ figures, 95% CI values and slope (SE) for 4b in the MES screenobtained 4h after intraperitoneal injection into rats were as follows:2.37, 1.39-3.57 and 2.65(0.76) while the corresponding TD₅₀ data were80.09,66.14-87.27 and 17.02(6.41). The protection afforded afterintraperitoneal administration of 125 and 250 mg/kg of 4b in the scPTZscreen was displayed in 0/2 and 1/10 rats.

Kindled Rat Test Using Compound 4b

The kindled rat test was undertaken by reported procedures (as indicatedabove). Compound 4b was administered orally and the animals challengedwith electrical stimuli 2h later. The ED₅₀ is the dose required toreduce seizures from stage 5 to stage 3 or less and these stages aredescribed as follows namely stage 1 is mouth and facial clonus, stage 2is stage 1 plus head nodding, stage 3 is stage 2 plus forelimb clonus,stage 4 is stage 3 plus rearing and stage 5 is stage 4 plus repeatedrearing and falling. The ED₅₀ (mg/kg), 95% CI and slope (SE) figures for4b were as follows: 3.93, 2.40-6.09 and 3.62(1.10). The ED₅₀ data(mg/kg, 95% CI in parentheses) and times of the test for three referencedrugs were as follows: phenytoin: >100, 0.25 h; carbamazepine: 28.90(7.72-75.59), 1h and valproate: 117.41 (67.98-189.02), 0.25h.

Effect of Chronic Oral Administration of 4b on Rat Livers

Rats were administered 100 mg/kg of 4b daily for 3 days. The livers wereremoved, weighed and the effect of 4b on the liver microsomal systemwere compared to control animals which received only the vehicle(sonicated 0.5% methylcellulose).²¹⁻²³

(VI) Evaluation of 4b and 5g in the Timed Intravenous PentylenetetrazoleTest

Compounds 4b and 5g in methylcellulose solution (0.5%) were injectedintraperitoneally into mice. The two doses used were the approximateED₅₀ values in the MES test and the TD₅₀ figures. After 1h, a solutionof pentylenetetrazole (0.5%), sodium chloride and sodium heparin (10 USPunits/mL) in water were infused into the tail veins of mice at a rate of0.37 mL/min (4b) and 0.34 mL/min (5g). The times from thecommencement-of the infusion until the appearances of the first twitchand also the onset of clonus were recorded for the test and controlanimals. From these data, the quantities of pentylenetetrazole infusedwas obtained. Ten animals were used as controls and for each doseadministered except for the 13 mg/kg dose of 4b in which case 9 animalswere employed. The figures for the times of the first twitch in seconds,quantity of pentylenetetrazole administered in mg/kg (SE) and p valueswere as follows: 4b(dose of 13 mg/kg): 32.2,32.3(1.4), >0.05;4b(dose of108 mg/kg):32.2, 32.6(0.8), >0.05; 5g(dose of 15 mg/kg):32.8,32.9(1.4), >0.05;5g(dose of 95 mg/kg): 34.6,34.6(1.5), >0.05. Therelevant data for the times to clonus in seconds, quantity ofpentylenetetrazole administered in mg/kg (SE) and p values were asfollows: 4b(dose of 13 mg/kg): 37.6, 37.6(1.5), >0.05;4b(dose of 108mg/kg): 41.5,42.1(1.4), <0.01;5g(15 mg/kg): 41.2,41.2(2.6), 0.05;5g(doseof 95 mg/kg): 44.4, 44.4(2.5), >0.05.

(VII) Evaluation of 4h and 5g Using Other Chemically Induced SeizureModels

Various doses of 4b and 5g were administered to mice 1h (4b) or 0.5 h(5g) before chemoconvulsant doses of bicuculline and picrotoxin weregiven subcutaneously to mice. Compound 4b was also examined forprotective effects after subcutaneous administration of strychnine. Inthe case of 4b, the number of animals protected in the subcutaneousbicuculline test at different doses (mg/kg) were as follows: 0/8(54),3/8(108) and 3/8(216). In the subcutaneous picrotoxin test, theprotection at various doses (mg/kg) were as follows: 1/8(27), 5/16(108),2/8(216). Compound 5g showed no effect in the 12-96 mg/kg dose range inthese two tests. The semicarbazone 4b afforded no protection in thesubcutaneous strychnine test using a dose range of 13.5-108 mg/kg. Twoanimals per dose were used except in the bicuculline and picrotoxintests for 4b in which cases, 8 or 16 animals per dose were employed.

EXAMPLE 3

The compounds having the structures shown in Table 4 were prepared. Thestructures of the listed compounds correspond to those shown in FIG. 3identified by the same first number (12, 13, 14, 15, 16, 17 or 18), withonly the substituents being identified in Table 4.

TABLE 4 Aryl Substituents, Physical Data and Anticonvulsant Evaluationafter Intraperitoneal Injection into Mice and Oral Administration toRats of the Compounds in Series 12-18^(a) intraperitoneal injection inmice^(b) MES acPTZ toxicity oral administration to rats^(c) m.p. yieldscreen screen screen dose MES screen compound R¹ R² (° C.) % 0.5 h 4 h0.5 h 4 h 0.5 h 4 h (mg/kg) 0.25 h 0.5 h 1 h 2 h 4 h 12a H F 240^(a) 65 30 100 — — — — 50 2 4 4 4 4 12b H H 224-225 60 100 300 — — — — 50 — 3 44 4 12c H Cl 225-226 40  30  30  30 — 300  30 50 4 4 4 4 4 12d H Br225-226 60  30  30 — — 300  30 50 1 4 4 4 4 12e H CH₃ 219-221 50  30 100— — — — 50 3 4 4 4 4 13a CH₃ H 169-171 60  30 100 — — 100 100  30 4 4 44 4 13b CH₃ F 182-184 74  30  30 100 — 300 100 12.5 — 4 4 4 4 13c CH₃ Cl192-194 60  30  30 —  30  30 100  30 3 4 4 4 4 13d CH₃ Br 195-197 30  30 30 300 — 300 100 12.5 1 3 4 4 4 13e C₂H₅ H 154-156 58  30 100 — — 100100  30 1 4 3 3 — 13f C₂H₅ F 170-172 72  30  30 100 — 300 100 12.5 — 2 44 4 13g C₂H₅ Cl 186-188 38  30 — 300 — 300 100 30 — 1 4 4 4 13h C₂H₅ Br184-186 38  30  30 100 — 300 100 12.5 — 2 4 4 4 14a CH₃ H 136-138 14 300— 300 — 300 — − − − − − − 14b CH₃ F 154-157 27 — — — — — —  30 1 1 3 3 214c CH₃ Cl 167-169 32 300 300 300 300 300 300 − − − − − − 14d CH₃ Br183-186 28 — — — — 300 — − − − − − − 14e C₂H₅ F 156-158 55 — — — — — 30012.5 — — — — — 14f C₂H₅ Cl 136-138 15 300 300 — — — — − − − − − − 14gC₂H₅ Br 155-157  5 — — — — — 300 − − − − − − 15a S H 226-227 40  30  30— — — 300 50 — 4 4 4 4 15b OCO H 237-238 70 — 300 — — — — 12.5 — — — — —15c OCO Cl 245-246 80 — 300 — — — — 12.5 1 — 1 — 2 15d OCH₂ H 212-213 52300 300 — 100 — — 12.5 — — 1 1 — 15e SO₂ H 254 40 — 300 — — — — − − − −− − 15f OSO₂ H 146 40  30  30  30 — 300 300 12.5 1 2 2 4 3 15g OSO₂ CH₃205-207 70 — — — — — — — — — — — — 16a H F 230-231 52  30  30  30 — 300100 12.5 1 3 4 4 4 16b H Cl 216 40 100  30 300 — — 100 50 1 4 4 4 4 16cH Br 212-213 30 100  30 — 300 — 300 12.5 0 1 3 4 4 16d H CH₃ 225-227 32 30  30 100 100 300 100 12.5 0 0 4 4 4 16e CH₃ H 208-210 60 100 100 300— — —  30 0 4 4 4 4 16f CH₃ F 204-207 91 100  30 — 300 300 300  30 3 4 44 4 16g C₂H₅ H 131-133 16  30  30 100 100 100 100  30 — 3 4 3 4 16h C₂H₅F 150-157 18  30 100 — — 100 100  30 0 0 2 3 3 17a S O 167 56  30  30 30  30 100  30 12.5 — 2 2 3 1 17b NH O 181-183 50 300  30  30 — 100 10012.5 — — — 1 2 17c S S 171-172 62 100 100 100 100 — 100 12.5 — 1 2 1 117d NH S 172-173 40 300 —  30  30 100 100 12.5 — — — 1 — 18a H O 176-17860 300 300 — 300 — 300 − − − − − − 18b CH₃ O 160 83  30  30 100 100 100100 12.5 1 4 2 2 1 18c NHNH₂ O 220 80 300 100 — 300 — 300  30 — — — — —18d CONH₂ O 253 75 — — — — 300 300 — — — — — — 18e H S 146-148 80 100100 — 300 — 300  30 1 — — — 1 Phenytoin − −  30  30 — — 100 100 − − − −− − Carbamazepine − −  30 100 100 300 100 300 − − − − − − Valproate − −— — 300 — — — − − − − − − ^(a)Doses of 30, 100 and 300 mg/kg wereadministered. The figures in the table indicate the minimum dose wherebybioactivity was demonstrated in half or more of the mice. The animalswere examined 0.5 h and 4 h after injections were made. The lines —indicate an absence of anticonvulsant activity and neurotoxicity.^(b)The figures in the table indicate the number of rats out of 4 whichwere protected. The lines — mean that no activity was demonstrated whilethe designation − reveals that the compound was not screened.

These compounds were synthesized as follows, although attempts toisolate 2-phenoxypropiophenone, required in the synthesis of compound 4(R¹═C₂H₅;R²═H), were unsuccessful; the reactions invariably leading tothe formation of a number of compounds. The intermediate aldehydes andketones were reacted with semicarbazide (13-16), thiosemicarbazide(17a,c), aminoguanidine (17b,d), formic acid hydrazide (18a,e), acetichydrazide (18b), carbohydrazide (18c) or oxamic hydrazide (18d).

Initial anticonvulsant evaluation of compounds 13-18 was undertaken asfollows. Doses of 30, 100 and 300 mg/kg were injected by theintraperitoneal route into mice and evaluated in the MES, scPTZ andneurotoxicity screens one half and four hours after administration. Theresults are presented in Table 4 above in addition to the data for 12a-ewhich is included for comparative purposes.

Quantitation of the activity of selected compounds was undertaken andthese results are indicated in Table 5.

TABLE 5 Quantitation of the Activity of Certain Compounds in the MES,acPTZ and Neurotoxicity Screens after Intraperitoneal Injection in MiceMES screen acPTZ screen neurotoxicity screen t ED₅₀(mg/kg) slope tED₅₀(mg/kg) slope t TD₅₀(mg/kg) slope PI* Compound (h) (95% CI) (SE) (h)(95% CI) (SE) (h) (95% CI) (SE) MES acPTZ 12a 1 12.86 8.28 1 >54 — 1108.03  3.69 8.40 — (10.54-17.09) (3.00) — —  (71.52-157.52) (0.96) 13a0.25 9.08 6.21 0.25 43.31 1.54 1 73.48 10.51 8.09 1.70  (6.45-11.31)(1.91) (18.36-112.07) (0.57) (64.32-86.40) (3.08) 13b 1 11.63 22.690.25 >80 — 2 60.74 45.21 5.22 — (10.96-12.48) (9.34) — — (58.92-63.84)(14.45) 13f 1  5.46 11.64 2 12.84 3.34 2 35.26 6.78 6.45 2.75(4.57-6.46) (3.74) (8.25-18.55) (1.16) (25.02-43.44) (2.05) 13g 4 11.0920.278 <100 <9.017 (10.367-12.583) (6.827) 15a 1 15.62 4.50 1 >46 — 2181.00  4.59 11.59 — (10.45-20.56) (1.36) — — (122.53-250.73) (1.27) 15f0.5 25.27 9.52 0.5 >100 — 1 113.00  17.38 4.47 — (2.150-29.87) (3.00) ——  (103.0-122.68) (5.73) 16a 1 12.37 6.372 1 >120 2 88.00 24.001 7.112<0.733  (9.247-16.128) (1.915) (83.311—94.847) (6.853) 16b 1 16.22 23.211 >120 — 2 53.18 5.90 3.28 — (14.63-17.59) (8.59) — — (41.42-72.54)(1.89) 16c 2 24.37 5.92 2 >200 — 2 122.57  6.92 5.03 — (18.45-30.93)(1.72) — — (101.63-149.51) (2.10) 16d 1 9.46 3.676 1 >300 4 196.52 12.821 20.776 <0.655  (6.353-13.026) (0.986) (174.429-226.477) (3.957)Phenytoin 2   6.48 12.4 2 >50 — 0.5 42.8 10.2 6.60 — (5.66-7.24) (3.60)— — (36.4-47.5) (3.13) Carbam- 0.25  9.85 20.8 0.25 >50 — 0.25 47.8 7.984.85 — azepine (8.77-10.7) (7.15) — — (39.2-59.2) (2.37) Valproate 0.25287 7.31 0.25 209 8.51 0.25 483 12.3 1.68 2.31 (237-359) (2.48)(176-249)  (2.69) (412-571) (4.01) *The protection index (PI) isobtained by dividing the TD₅₀ figues by the ED₅₀ values.

Evaluation of most of the semicarbazones and analogs in the MES andneurotoxicity tests after oral administration to rats was performed. Atthe doses indicated in Table 4, neurotoxicity was absent and some of thecompounds examined in the scPTZ screen were either inactive or affordedonly minimal protection. Hence only the MES data are presented in Table4. The ED₅₀ figures of several compounds in the rat oral MES screen aregiven in Table 6.

TABLE 6 Quantitation of the Activity of Selected Compounds in the MESand Neurotoxicity Screens after Oral Administration to Rats MES ScreenNeurotoxicity screen ED₅₀(mg/kg) slope TD₅₀(mg/kg) slope Compound t (h)(95% CI) (SE) t(h) (95% CI) (SE) PI^(a) 12a ^(b) 2 1.59 3.17¼-24^(c) >500 — >315 (1.01-2.25) (0.84) — — 13a 4 9.73 3.844 — — — — (6.440-14.141) (1.300) 13b 2 3.37 5.74 2 108.77 4.82 32.3 (2.37-4.72)(1.80)  (80.26-177.74) (1.82) 13c 4 2.92 5.774 4 <500 — <170.73(2.203-3.464) (1.595) 13d 4 1.52 3.600 — >500   >328.28 (0.989-2.300)(1.024) 13e 0.5 23.08  3.14 — — — — (14.33-36.64) (0.92) — — 13f 2 4.253.67 4 >72(<240) −>16.9  (<56.436) (2.89-5.97) (1.04) — — 13g 2 2.892.035 0 >500 — >172.81 (1.568-5.294) (0.594) 13h 4 4.39 4.206 (2.67-5.833) (1.279) 14b 2 43.37  2.287 (25.078-66.343) (0.569) 15a 44.29 6.02 ¼-24 >496 — >115.6 (3.20-5.24) (2.00) — — 16a 2 4.98 3.92 4183.05 2.49 36.8 (3.24-7.01) (1.10) (100.59-338.35) (0.86) 16f 2 9.115.285 — — — —  (6.185-11.658) (1.496) 16g 2 18.58  5.238 — — — —(14.195-25.038) (1.674) 18b 0.5 18.66  3.93 2 >125 — >6.70 (12.40-27.60)(1.11) — — — Phenytoin 2 23.2 15.1  ¼-24^(c) >500 — >21.6 (21.4-25.4)(4.28) — — Carbamazepine 1 3.57 3.84 1  361 11.4  101 (2.41-4.72) (1.15)(319-402) (2.96) Valproate 0.5 395 8.13   0.5  859 6.57 2.17 (332-441)(2.76)  (719-1148) (2.17) ^(a)The letters PI refer to the protectionindex viz TD₅₀/ED₅₀. ^(b)Data for this compound were taken fromreference 1. ^(c)The compound was examined 0.25, 0.5, 1, 2, 4, 6, 8 and24 h after administration.

The final pharmacological evaluation of representative compounds wasundertaken using an epileptic chicken model.⁶ In this case, theconvulsions which are induced by intermittent photic stimulations havebeen shown to be prevented by a number of anticonvulsants at bloodlevels similar to those used in humans. Two series of compounds wereexamined with the aim of observing whether oxygen or sulfur is apreferable spacer atom between the two aryl rings and also to comparethe ED₅₀ figures with those obtained in the rat oral and mouseintraperitoneal screens. The ED₅₀ values of the ethers 12a-d were 1.5,2.5, 1.0 and 2.0 mg/kg respectively and for the thioethers bearing thesame aryl substitution pattern namely 16a,15a,16b,c, the figures were1.5, 2.5, 1.0 and 1.5 mg/kg respectively. Hence potencies are unaffectedby whether oxygen or sulfur are used as the spacer group. The ED₅₀values of 12a,15a,16a in the rat oral screen are in the 1-5 mg/kg rangewhereas for 12a,15a,16b,c the figures in the mouse intraperitoneal testare approximately 15-25 mg/kg. Hence the results from the epilepticchicken model are comparable with the data provided in the rat oralscreen.

What we claim is:
 1. A compound of the general formula I:

wherein R¹, R², R³ and R⁴ may be the same or different and eachrepresents hydrogen, halo, C₁₋₉alkyl, C₃₋₉cycloalkyl, cyano, C₁₋₉alkoxyor C₆₋₁₀aryloxy; R⁵ represents hydrogen, C₁₋₉alkyl, C₃₋₉cycloalkyl orC₆₋₁₀aryl; and X is oxygen or sulfur; with the proviso that: a) if X issulfur, then at least one of R¹ and R² is other than hydrogen or atleast one of R³ and R⁴ is fluoro, C₁₋₉alkyl, C₃₋₉cycloalkyl, cyano,C₁₋₉alkoxy or C₆₋₁₀aryloxy; and b) if X is oxygen, R⁵ is hydrogen,methyl, or ethyl, and if one of R¹ and R² is chloro or methoxy or if oneof R³ and R⁴ is methyl, then the other of R¹ and R² or the other of R³and R⁴ is other than hydrogen; and c) if X is oxygen, R⁵ is hydrogen,methyl or ethyl, and if R¹ and R² are both hydrogen, then at least oneof R³ and R⁴ is other than hydrogen and methyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein atleast one of R¹ and R² represents fluoro, R³ and R⁴ are each hydrogen,R⁵ is hydrogen or C₁₋₃alkyl, and X is O.
 3. A compound according toclaim 1 wherein at least one of R¹ and R² represent fluoro, R⁵ ishydrogen, and X represents oxygen.
 4. 4-(4′-Fluorophenoxy)benzaldehydesemicarbazone or a pharmaceutically-acceptable salt thereof.
 5. A methodof preparing a compound of general formula I:

wherein: R¹, R², R³ and R⁴ may be the same or different and eachrepresents a hydrogen or halogen atom, or a C₁₋₉alkyl, C₃₋₉cycloalkyl,cyano, C₁₋₉alkoxy or C₆₋₁₀aryloxy group; R⁵ represents a hydrogen atomor a C₁₋₉alkyl, C₃₋₉cycloalkyl or C₆₋₁₀aryl group; and X is oxygen orsulfur; except that R¹, R², R³, R⁴ and R⁵ may not all be hydrogen; withthe provisos that: (a) if X is sulfur, then at least one of R ¹ and R ²is other than hydrogen or at least one of R ³ and R ⁴ is fluoro, C ₁₋₉alkyl, C ₃₋₉ cycloalkyl, cyano, C ₁₋₉ alkoxy or C ₆₋₁₀ aryloxy; and (b)if X is oxygen, and R ⁵ is hydrogen, methyl, or ethyl, and one of R ¹and R ² is chloro, then (i) the other of R ¹ and R ² is other thanhydrogen or chloro, or (ii) at least one of R ³ and R ⁴ is other thanhydrogen; and (c) if X is oxygen, and R ⁵ is hydrogen, methyl, or ethyl,and one of R ¹ and R ² is methoxy, then (i) the other of R ¹ and R ² isother than hydrogen or methoxy, or (ii) at least one of R ³ and R ⁴ isother than hydrogen; and (d) if X is oxygen, and R ⁵ is hydrogen,methyl, or ethyl, and one of R ¹ and R ² is methyl, then (i) the otherof R ¹ and R ² is other than hydrogen or (ii) at least one of R ³ and R⁴ is other than hydrogen; and (e) if X is oxygen, R ⁵ is hydrogen,methyl or ethyl, and R ¹ and R ² are both hydrogen, then at least one ofR ³ and R ⁴ is other than hydrogen and methyl; which method comprisesforming an intermediate aryloxy- or arylthio-benzaldehydes or ketones byreacting a corresponding (thio)phenol with fluorobenzaldehyde or afluoroaryl ketone in a solvent in the presence of potassium carbonate attemperatures in the range of 100° to 200° C. under a non-oxidizing gas,extracting the intermediate and then reacting the intermediate withsemicarbazide and collecting the resulting precipitate of the desiredcompound.
 6. A method of treating a human or animal patient for adisorder of the central nervous system, comprising administering to saidpatient an effective amount of a compound having the general formula I:

wherein: R¹, R², R³ and R⁴ may be the same or different and eachrepresents hydrogen, halo, C₁₋₉alkyl, C₃₋₉cycloalkyl, cyano, C₁₋₉alkoxyor C₆₋₁₀aryloxy; R⁵ represents hydrogen, C₁₋₉alkyl, C₃₋₉cycloalkyl orC₆₋₁₀aryl; and X is oxygen or sulfur; with the proviso that; : a) atleast one of R¹, R², R³ or R⁴ is other than hydrogen, or b) R⁵ is otherthan hydrogen, methyl and ethyl; or a pharmaceutically acceptable saltthereof.
 7. A method according to claim 6 wherein said disorder exhibitsconvulsions or seizures.
 8. A method according to claim 6 wherein saiddisorder exhibits epileptic seizures.
 9. A compound of claim 1 which isselected from the group consisting of 4-(4-bromophenoxy)benzaldehydesemicarbazone; 4-(4-iodophenoxy)benzaldehyde semicarbazone;4-(4-methylphenoxy)benzaldehyde semicarbazone;4-(4-cyanophenoxy)benzaldehyde semicarbazone;4-(2-fluorophenoxy)benzaldehyde semicarbazone;4-(3-fluorophenoxy)benzaldehyde semicarbazone;4-(2,3-difluorophenoxy)benzaldehyde semicarbazone;4-(2,4-difluorophenoxy)benzaldehyde semicarbazone;4-(2,5-difluorophenoxy)benzaldehyde semicarbazone;4-(2,6-difluorophenoxy)benzaldehyde semicarbazone;4-(3,4-difluorophenoxy)benzaldehyde semicarbazone;4-(3,4-dichlorophenoxy)benzaldehyde semicarbazone;4-(4-chloro-2-fluorophenoxy)benzaldehyde semicarbazone;4-(2-chloro-4-fluorophenoxy)benzaldehyde semicarbazone;4-(2-bromo-4-fluorophenoxy)benzaldehyde semicarbazone;4-(2-methylphenoxy)benzaldehyde semicarbazone;4-(3-methylphenoxy)benzaldehyde semicarbazone;4-(4-ethylphenoxy)benzaldehyde semicarbazone;4-(4-n-propylphenoxy)benzaldehyde semicarbazone;4-(4-s-butylphenoxy)benzaldehyde semicarbazone;4-(4-t-butylphenoxy)benzaldehyde semicarbazone;4-(4-fluorophenoxy)acetophenone semicarbazone;4-(4-bromophenoxy)acetophenone semicarbazone;4-(4-fluorophenoxy)propiophenone semicarbazone;4-(4-bromophenoxy)propiophenone semicarbazone;4-(4-fluorophenylmercapto)benzaldehyde semicarbazone;4-(4-chlorophenylmercapto)benzaldehyde semicarbazone;4-(4bromophenylmercapto)benzaldehyde semicarbazone;4-(4-methylphenylmercapto)benzaldehyde semicarbazone; and4(4-fluorophenylmercapto)acetophenone semicarbazone.
 10. A compositioncomprising the compound of any one of claims 1-4 and 9, and apharmaceutically acceptable diluent, excipient or carrier.
 11. A methodof treating a human or animal patient for a disorder of the centralnervous system comprising administering to said patient an effectiveamount of a compound of any one of claims 1-4 and 9, or apharmaceutically acceptable salt thereof.
 12. A method according toclaim 11, wherein said disorder exhibits convulsions or seizures.
 13. Amethod according to claim 12, wherein said disorder exhibits epilepticseizures.
 14. A method according to claim 6, wherein said compound isadministered as part of a composition comprising a pharmaceuticallyacceptable carrier.
 15. A method according to claim 11, wherein saidcompound is administered as part of a composition comprising apharmaceutically acceptable carrier.
 16. A method according to claim 6,wherein X is oxygen.
 17. A method according to claim 6, wherein one ofR¹ and R ² is halogen, and the other of R ¹ and R ² is hydrogen orhalogen, R ³ and R ⁴ are each hydrogen, R ⁵ is hydrogen or C ₁₋₃ alkyl,and X is O or S.
 18. A method according to claim 17, wherein at leastone of R¹ and R ² is fluoro.
 19. A method according to claim 17, whereinX is O.
 20. A method according to claim 6, wherein said compoundpossesses an ED₅₀ from 1 to 5 mg/kg in a maximal electroshock screen inrate.
 21. The method according to claim 20, wherein said compoundpossesses an ED₅₀ from 2 to 3 mg/kg in a maximal electroshock screen inrats.
 22. A compound of general formula I:

or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² areindependently hydrogen or halogen; R ³ and R ⁴ are each hydrogen; R ⁵ ishydrogen or C ₁₋₃ alkyl; and X is O or S; provided that R ¹ and R ² arenot both hydrogen, R ¹ and R ² do not consist of hydrogen and chloro,and R ¹ and R ² are not both chloro.
 23. A compound according to claim22, wherein X is O.
 24. A compound according to claim 22, wherein atleast one of R¹ and R ² is fluoro.
 25. A compound according to claim 22,wherein R⁵ is hydrogen.
 26. A compound selected from the groupconsisting of: 4 -( 4 -bromophenoxy)benzaldehyde semicarbazone; and 4 -(4 -iodophenoxy)benzaldehyde semicarbozone; or a pharmaceuticallyacceptable salt thereof.
 27. A compound selected from the groupconsisting of: 4 -( 2 -fluorophenoxy)benzaldehyde semicarbazone; 4 -( 3-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,3-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,4-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,5-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,6-difluorophenoxy)benzaldehyde semicarbazone; and 4 -( 3,4-difluorophenoxy)benzaldehyde semicarbazone; or a pharmaceuticallyacceptable salt thereof.
 28. A compound selected from the groupconsisting of: 4 -( 4 -chloro- 2 -fluorophenoxy)benzaldehydesemicarbazone; 4 -( 2 -chloro- 4 -fluorophenoxy)benzaldehydesemicarbazone; and 4 -( 2 -bromo- 4 -fluorophenoxy)benzaldehydesemicarbazone; or a pharmaceutically acceptable salt thereof.
 29. Acompound selected from the group consisting of: 4 -( 4-fluorophenoxy)acetophenone semicarbazone; 4 -( 4-bromophenoxy)acetophenone semicarbazone; 4 -( 4-fluorophenoxy)propiophenone semicarbazone; 4 -( 4-bromophenoxy)propiophenone semicarbazone; 4 -( 4-fluorophenylmercapto)benzaldehyde semicarbazone; 4 -( 4-bromophenylmercapto)benzaldehyde semicarbazone; and 4 -( 4-fluorophenylmercapto)acetophenone semicarbazone; or a pharmaceuticallyacceptable salt thereof.
 30. A compound of general formula I:

or a pharmaceutically acceptable salt thereof, wherein: R ¹ , R ² , R ³and R ⁴ are independently hydrogen or halogen; R ⁵ is hydrogen; and X isO; provided that R ¹ and R ² are not both hydrogen.
 31. The compound 4-(4 -chlorophenoxy)benzaldehyde semicarbazone or apharmaceutically-acceptable salt thereof.
 32. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³and R ⁴ may be the same or different and each represents hydrogen, halo,C ₁₋₉ alkyl, C ₃₋₉ cycloalkyl, cyano, C ₁₋₉ alkoxy or C ₆₋₁₀ aryloxy; R⁵ represents hydrogen, C ₁₋₉ alkyl, C ₃₋₉ cycloalkyl or C ₆₋₁₀ aryl; andX is oxygen or sulfur; with the provisos that: (a) if X is sulfur, thenat least one of R ¹ and R ² is other than hydrogen or at least one of R³ and R ⁴ is fluoro, C ₁₋₉ alkyl, C ₃₋₉ cycloalkyl, cyano, C ₁₋₉ alkoxyor C ₆₋₁₀ aryloxy; and (b) if X is oxygen, and R ⁵ is hydrogen, methyl,or ethyl, and one of R ¹ and R ² is chloro, then (i) the other of R ¹and R ² is other than hydrogen or chloro, or (ii) at least one of R ³and R ⁴ is other than hydrogen; and (c) if X is oxygen, and R ⁵ ishydrogen, methyl, or ethyl, and one of R ¹ and R ² is methoxy, then (i)the other of R ¹ and R ² is other than hydrogen or methoxy, or (ii) atleast one of R ³ and R ⁴ is other than hydrogen; and (d) if X is oxygen,and R ⁵ is hydrogen, methyl, or ethyl, and one of R ¹ and R ² is methyl,then (i) the other of R ¹ and R ² is other than hydrogen or (ii) atleast one of R ³ and R ⁴ is other than hydrogen; and (e) if X is oxygen,R ⁵ is hydrogen, methyl or ethyl, and R ¹ and R ² are both hydrogen,then at least one of R ³ and R ⁴ is other than hydrogen and methyl. 33.A compound according to claim 32, wherein at least one of R¹ and R ²represents fluoro, R ³ and R ⁴ are each hydrogen, R ⁵ is hydrogen or C₁₋₃ alkyl, and X is oxygen.
 34. A compound according to claim 32,wherein at least one of R¹ and R ² represent fluoro, R ⁵ is hydrogen,and X represents oxygen.
 35. 4-( 4 -Fluorophenoxy)benzaldehydesemicarbazone or a pharmaceutically acceptable salt thereof.
 36. Thecompound of claim 32, wherein said compound is selected from the groupconsisting of: 4 -( 4 -bromophenoxy)benzaldehyde semicarbazone; 4 -( 4-iodophenoxy)benzaldehyde semicarbazone; 4 -( 4-cyanophenoxy)benzaldehyde semicarbazone; 4 -( 2-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 3-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,3-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,4-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,5-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 2,6-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 3,4-difluorophenoxy)benzaldehyde semicarbazone; 4 -( 4 -chloro- 2-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 2 -chloro- 4-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 2 -bromo- 4-fluorophenoxy)benzaldehyde semicarbazone; 4 -( 4-ethylphenoxy)benzaldehyde semicarbazone; 4 -( 4-n-propylphenoxy)benzaldehyde semicarbazone; 4 -( 4-s-butylphenoxy)benzaldehyde semicarbazone; 4 -( 4-t-butylphenoxy)benzaldehyde semicarbazone; 4 -( 4-fluorophenoxy)acetophenone semicarbazone; 4 -( 4-bromophenoxy)acetophenone semicarbazone; 4 -( 4-fluorophenoxy)propiophenone semicarbazone; 4 -( 4-bromophenoxy)propiophenone semicarbazone; 4 -( 4-fluorophenylmercapto)benzaldehyde semicarbazone; 4 -( 4-chlorophenylmercapto)benzaldehyde semicarbazone; 4 -( 4-bromophenylmercapto)benzaldehyde semicarbazone; 4 -( 4-methylphenylmercapto)benzaldehyde semicarbazone; and 4 -( 4-fluorophenylmercapto)benzaldehyde semicarbazone.
 37. 4-( 3,4-Dichlorophenoxy)benzaldehyde semicarbazone or a pharmaceuticallyacceptable salt thereof.
 38. A compound selected from the groupconsisting of: 4 -( 2 -methylphenoxy)benzaldehyde semicarbazone; 4 -( 3-methylphenoxy)benzaldehyde semicarbazone; and 4 -( 4-methylphenoxy)benzaldehyde semicarbazone; or a pharmaceuticallyacceptable salt thereof.
 39. A composition comprising the compound ofany one of claims 32-38 and a pharmaceutically acceptable diluent,excipient or carrier.
 40. A method of treating a human or animal patientfor a disorder of the central nervous system comprising administering tosaid patient an effective amount of a compound of any one of claims32-38, or a pharmaceutically acceptable salt thereof.
 41. A methodaccording to claim 40, wherein said disorder exhibits convulsions orseizures.
 42. A method according to claim 41, wherein said disorderexhibits epileptic seizures.
 43. A method according to claim 40, whereinsaid compound is administered as part of a composition comprising apharmaceutically acceptable carrier.
 44. The method of claim 5, whereinsaid method comprises: (i) forming an intermediate aryloxy- orarylthio-benzaldehyde or ketone by reacting a corresponding (thio)phenolwith fluorobenzaldehyde or a fluoroaryl ketone in a solvent in thepresence of potassium carbonate at temperatures in the range of 100° to200° C. under nitrogen; (ii) monitoring for formation of saidintermediate by thin layer chromatography; (iii) adding water to thesolvent containing said intermediate; (iv) partitioning the intermediateinto chloroform to form an intermediate solution; (v) washing theintermediate solution with dilute aqueous sodium hydroxide; (vi) dryingthe washed intermediate solution over anhydrous magnesium sulfate; (vii)removing the chloroform from the dried and washed intermediate solutionby solvent evaporation under vacuum to form an oil; (viii) distillingsaid oil under reduced pressure to provide an extracted intermediate;(ix) reacting the extracted intermediate with semicarbazide; and (x)collecting the resulting precipitate of the desired compound.
 45. Themethod of claim 44, wherein at (i) said solvent is dimethylacetamide.46. The method of claim 44, wherein at (i) said temperature is about155° C.
 47. The method of claim 44, wherein at (i) the molar ratio ofsaid corresponding (thio)phenol and said fluorobenzaldehyde orfluoroaryl ketone is 0.15:0.14.
 48. The method of claim 44, wherein at(v) said dilute aqueous sodium hydroxide is about 4 % sodium hydroxideand about 96 % water (weight/volume).